Alternative titles; symbols
SNOMEDCT: 417183007; ORPHA: 98970; DO: 0060448;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q34 | Corneal fleck dystrophy | 121850 | Autosomal dominant | 3 | PIKFYVE | 609414 |
A number sign (#) is used with this entry because of evidence that fleck corneal dystrophy (CFD) is caused by heterozygous mutation in the PIKFYVE gene (609414) on chromosome 2q34.
Fleck corneal dystrophy (CFD) is a rare autosomal dominant disease characterized by numerous tiny, dot-like white flecks scattered in all layers of the corneal stroma. Typically, the stroma located in between the flecks is clear, and the endothelium, the epithelium, Bowman layer, and Descemet membrane are normal. Patients are usually asymptomatic with normal vision, yet a small number of patients report the sensation of a minor photophobia. The flecks in CFD can appear as early as 2 years of age, or sometimes even at birth, and appear not to progress significantly throughout life. Histologically, the corneal flecks appear to correspond to abnormal keratocytes swollen with membrane-limited intracytoplasmic vesicles containing complex lipids and glycosaminoglycans (summary by Kawasaki et al., 2012).
Francois and Neetens (1957) described an autosomal dominant stromal dystrophy of the cornea characterized by scattered tiny white flecks occurring at all levels of the stroma, with configurations varying from semicircular to wreath-like, curvilinear, or punctate. Others (e.g., Gillespie and Covelli, 1963; Patten et al., 1976) referred to the disorder as hereditary fleck dystrophy of the cornea (French adjective 'mouchetee'). Nicholson et al. (1977) reported a family with affected persons in 3 generations, including male-to-male transmission, and described histologic, biochemical, and ultrastructural findings.
Jiao et al. (2003) noted that flecks in the cornea may appear as early as 2 years of age or even congenitally, but do not appear to progress significantly throughout life. The endothelium, epithelium, Bowman layer, and Descemet membrane are normal. Although CFD may occasionally cause mild photophobia, patients are typically asymptomatic and have normal vision. The disease is most often found on routine examination (Akova et al., 1994). Variable expressivity is a feature (Goldberg et al., 1977), with asymmetric involvement of the eyes and even unilateral nonpenetrance.
Kawasaki et al. (2012) studied a 63-year-old Japanese woman who presented with a 1-month history of decreased vision and metamorphopsia in her right eye, which appeared to be due to a transient focal retinal detachment caused by traction of the posterior vitreous membrane. Ophthalmologic examination revealed bilateral small, dot-like, white fleck opacities scattered in all layers of the corneal stroma. The opacities were more prominent at the corneal periphery but were found throughout the entire cornea. The opacities were almost invisible under diffuse illumination, but became more apparent with slit-lamp illumination or iris retroillumination. Her retinal problem spontaneously ameliorated over a 2-week period with improvement of her visual acuity, indicating that the decrease in visual acuity of her right eye at presentation was not due to the corneal opacities. Kawasaki et al. (2012) noted that the disorder may be underdiagnosed due to the subtle nature of the opacities and lack of associated symptoms.
The transmission pattern of CFD in the families reported by Li et al. (2005) was consistent with autosomal dominant inheritance.
Jiao et al. (2003) reported linkage of the CFD locus to chromosome 2q35. Multipoint analysis demonstrated a maximum lod score of 5.0 at a point midway between D2S2289 and D2S325.
In 10 unrelated families of European origin, including the original 4 families studied by Jiao et al. (2003), Li et al. (2005) refined linkage of the CFD locus to a 24-cM interval flanked by D2S2289 and D2S126 and containing approximately 18 Mb.
Li et al. (2005) performed sequence analysis of the PIKFYVE gene (609414) and identified missense, frameshift, and/or protein-truncating mutations in 8 of 10 families with CFD studied. The protein encoded by PIKFYVE is a member of the phosphoinositide 3-kinase family and regulates the sorting and traffic of peripheral endosomes that contain lysosomally directed fluid phase cargo, by controlling the morphogenesis and function of multivesicular bodies. The histologic and clinical characteristics of patients with CFD were considered consistent with the biochemical studies of PIKFYVE that indicated a role in endosomal sorting.
In a 63-year-old Japanese woman with fleck corneal dystrophy, Kawasaki et al. (2012) identified heterozygosity for a 4-bp deletion in the PIKFYVE gene (609414.0003). The mutation was not found in her unaffected sister or in 92 Japanese controls.
In 2 women with fleck corneal dystrophy, Gee et al. (2015) identified heterozygous mutations in the PIKFYVE gene: a frameshift (609414.0004) and a 2-exon deletion (609414.0005).
Akova, Y. A., Unlu, N., Duman, S. Fleck dystrophy of the cornea: a report of cases from three generations of a family. Europ. J. Ophthal. 4: 123-125, 1994. [PubMed: 7950337] [Full Text: https://doi.org/10.1177/112067219400400209]
Francois, J., Neetens, A. Nouvelle dystrophie heredofamiliale du parenchyme corneen (heredo-dystrophie mouchetee). Bull. Soc. Belge Ophtal. 114: 641-646, 1957. [PubMed: 13446668]
Gee, J. A., Frausto, R. F., Chung, D.-W. D., Tankmonkongvoragul, C., Le, D. J., Wang, C., Han, J., Aldave, A. J. Identification of novel PIKFYVE gene mutations associated with Fleck corneal dystrophy. Molec. Vision 21: 1093-1100, 2015. [PubMed: 26396486]
Gillespie, F., Covelli, B. Fleck (mouchetee) dystrophy of the cornea: report of a family. Sth. Med. J. 56: 1265-1267, 1963. [PubMed: 14078376] [Full Text: https://doi.org/10.1097/00007611-196311000-00014]
Goldberg, M. F., Krimmer, B., Sugar, J., Sewell, J., Wong, P. Variable expression in flecked (speckled) dystrophy of the cornea. Ann. Ophthal. 9: 889-896, 1977. [PubMed: 302662]
Jiao, X., Munier, F. L., Schorderet, D. F., Zografos, L., Smith, J., Rubin, B., Hejtmancik, J. F. Genetic linkage of Francois-Neetens fleck (mouchetee) corneal dystrophy to chromosome 2q35. Hum. Genet. 112: 593-599, 2003. [PubMed: 12607114] [Full Text: https://doi.org/10.1007/s00439-002-0905-1]
Kawasaki, S., Yamasaki, K., Nakagawa, H., Shinomiya, K., Nakatsukasa, M., Nakai, Y., Kinoshita, S. A novel mutation (p.Glu2389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy. Molec. Vis. 18: 2954-2960, 2012. [PubMed: 23288988]
Li, S., Tiab, L., Jiao, X., Munier, F. L., Zografos, L., Frueh, B. E., Sergeev, Y., Smith, J., Rubin, B., Meallet, M. A., Forster, R. K., Hejtmancik, J. F., Schorderet, D. F. Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am. J. Hum. Genet. 77: 54-63, 2005. [PubMed: 15902656] [Full Text: https://doi.org/10.1086/431346]
Nicholson, D. H., Green, W. R., Cross, H. E., Kenyon, K. R., Massof, D. A clinical and histopathological study of Francois-Neetens speckled corneal dystrophy. Am. J. Ophthal. 83: 554-560, 1977. [PubMed: 141212] [Full Text: https://doi.org/10.1016/0002-9394(77)90566-9]
Patten, J. T., Hyndiuk, R. A., Donaldson, D. D., Herman, S. J., Ostler, H. B. Fleck (mouchetee) dystrophy of the cornea. Ann. Ophthal. 8: 25-32, 1976. [PubMed: 1082286]